When It Comes to LDL-C, “You Really Can’t Be Too Low”

MedicalResearch.com Interview with:

Marc S. Sabatine, MD, MPH  Chairman | TIMI Study Group  Lewis Dexter, MD, Distinguished Chair in Cardiovascular Medicine Brigham and Women's Hospital  Professor of Medicine | Harvard Medical School

Dr. Marc Sabatine

Marc S. Sabatine, MD, MPH
Chairman | TIMI Study Group
Lewis Dexter, MD, Distinguished Chair in Cardiovascular Medicine
Brigham and Women’s Hospital
Professor of Medicine | Harvard Medical School

MedicalResearch.com: What is the background for this study? What are the main findings? 

Response: Low-density lipoprotein cholesterol (LDL-C) is a well-established risk factor for cardiovascular disease.

The initial statin trials studied patients with high levels of LDL-C, and showed a benefit by lowering LDL-C.

We and others did studies in patients with so-called “average” levels of LDL-C (120-130 mg/dL), and also showed clinical benefit with lowering.

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Not All HDL Cholesterol is Good – Size Matters

MedicalResearch.com Interview with:

Samar R. El Khoudary, PhD, MPH, BPharm, FAHA Associate Professor, Epidemiology PITT Public Health Epidemiology Data Center University of Pittsburgh Pittsburgh, PA 15260 

Dr. El Khoudary

Samar R. El Khoudary, Ph.D., M.P.H. BPharm, FAHA
Associate Professor
Department of Epidemiology
University of Pittsburgh Graduate School of Public Health

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: The background for this study is based on the current measurements used to determine cardiovascular disease risk in postmenopausal women. Higher levels of HDL “good cholesterol” as measured by the widely available clinical test, HDL-Cholesterol, may not always be indicative of a lower risk of cardiovascular disease in postmenopausal women.

HDL is a family of particles found in the blood that vary in sizes, cholesterol contents and function. HDL particles can become dysfunctional under certain conditions such as chronic inflammation. HDL has traditionally been measured as the total cholesterol carried by the HDL particles, known as HDL cholesterol. HDL cholesterol, however, does not necessarily reflect the overall concentration, the uneven distribution, or the content and function of HDL particles.

We looked at 1,138 women aged 45 through 84 enrolled across the U.S. in the Multi-Ethnic Study of Atherosclerosis (MESA), a medical research study sponsored by the National Heart, Lung and Blood Institute of the National Institutes of Health (NIH). MESA began in 1999 and is still following participants today. We assessed two specific measurements of HDL: the number and size of the HDL particles and total cholesterol carried by HDL particles. Our study also looked at how age when women transitioned into post menopause, and the amount of time since transitioning, may impact the expected cardio-protective associations of HDL measures.

Our study points out that the traditional measure of the good cholesterol, HDL cholesterol, fails to portray an accurate depiction of heart disease risk for postmenopausal women. We reported a harmful association between higher HDL cholesterol and atherosclerosis risk that was most evident in women with older age at menopause and who were greater than, or equal to, 10 years into post menopause. In contrast to HDL cholesterol, a higher concentration of total HDL particles was associated with lower risk of atherosclerosis. Additionally, having a high number of small HDL particles was found beneficial for postmenopausal women. These findings persist irrespective of age and how long it has been since women became postmenopausal.

On the other hand, large HDL particles are linked to an increased risk of cardiovascular disease close to menopause. Women are subject to a variety of physiological changes in their sex hormones, lipids, body fat deposition and vascular health as they transition through menopause. We are hypothesizing that the decrease of estrogen, a cardio-protective sex hormone, along with other metabolic changes, can trigger chronic inflammation over time, which may alter the quality of HDL particles. Future studies should test this hypothesis.

The study findings indicate that measuring size and number of HDL particles can better reflect the well-known cardio-protective features of the good cholesterol in postmenopausal women. Continue reading

Individuals With Very High Levels of Lipoprotein(a) May Benefit Most From LDL(a)-Lowering Drugs

MedicalResearch.com Interview with:

Dr. Stephen Burgess PhD Programme Leader at the Medical Research Council Biostatistics Unit University of Cambridge

Dr. Burgess

Dr. Stephen Burgess PhD
Programme Leader at the Medical Research Council Biostatistics Unit
University of Cambridge

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Lipoprotein(a) is a lipoprotein subclass, and an important biomarker for coronary heart disease. As a clinical biomarker, it has a similar story to LDL-cholesterol (“bad” cholesterol), in that it is thought to be a causal risk factor for coronary heart disease, and so is a potential target for drug development. However, while drugs that lower LDL-cholesterol, such as statins, have been successful in reducing coronary heart disease risk, drugs that lower lipoprotein(a) have not as yet been successful. New drugs are currently in development that specifically target lipoprotein(a) and can lower lipoprotein(a) concentrations by 80-90%. We performed this study to investigate whether these drugs are likely to be successful in reducing coronary heart disease risk.

We compared individuals with naturally-occurring genetic variants that predispose them to a higher or lower lifetime concentration of lipoprotein(a) as a way of mimicking a randomized controlled trial. This approach has previously been undertaken for other biomarkers, including LDL-cholesterol. We found that having 10mg/dL lower genetically-predicted concentration of lipoprotein(a) was associated with a 5.8% reduction in coronary heart disease risk.

However, associations between genetically-predicted LDL-cholesterol and coronary heart disease risk are quantitatively much stronger than the proportional effect of LDL-cholesterol lowering on coronary heart disease risk as estimated by statin trials. This is because differences in genetic variants reflect lifelong changes in LDL-cholesterol, whereas statin trials only lower LDL-cholesterol for a few years. Hence, using the ratio between the genetic and trial estimates for LDL-cholesterol, we estimate that lowering lipoprotein(a) by 10mg/dL in a short-term clinical trial would only reduce coronary heart disease risk by 2.7%. To obtain the same reduction in coronary heart disease risk of around 20% as observed in statin trials, lipoprotein(a) would have to be lowered by around 100mg/dL. This explains why previous trials of less specific and less potent lipoprotein(a)-lowering drugs have failed to demonstrate benefit.

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African Americans Less Likely To Be Treated With Statins

MedicalResearch.com Interview with:

Michael G. Nanna, MD Fellow, Division of Cardiology Duke University Medical Center Durham, NC

Dr. Nanna

Michael G. Nanna, MD
Fellow, Division of Cardiology
Duke University Medical Center
Durham, NC

MedicalResearch.com: What is the background for this study?

Response: We know that African Americans are at higher risk for cardiovascular disease than white patients. We also know that African American individuals have been less likely to receive statin therapy compared to white individuals in the past. However, the reasons underlying these racial differences in statin treatment are poorly understood. We set out to determine if African American individuals in contemporary practice are treated less aggressively than whites and, if so, we wanted to investigate potential reasons why this might be the case.

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LPA Gene Variants Linked To Cardiac Events Despite Statins

MedicalResearch.com Interview with:

Wei-Qi Wei, MD, PhD Assistant Professor Department of Biomedical Informatics Vanderbilt University Nashville, TN 37203

Dr. Wei-Qi Wei

Wei-Qi Wei, MD, PhD
Assistant Professor
Department of Biomedical Informatics
Vanderbilt University
Nashville, TN 37203

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: The study was motived by the clinical observation that some patients develop coronary heart disease events despite taking statins, one of our most effective drugs to reduce cardiovascular risk. We collected data within the eMERGE network of people taking statins and monitored them for development of coronary heart disease events over time.  We  conducted a genome-wide association study of those with events compared to those without events.

Our results showed that single nucleotide polymorphisms (SNPs) on the LPA gene were associated with a significantly increased risk of coronary heart disease events. Individuals with the variant were 50% more likely to have an event. More importantly, even among patients who achieved ideal on-treatment LDL cholesterol levels (<70 mg/dL), the association remained statistically significant.

We then did a phenome-wide association study to see if other diseases or conditions were associated with these LPAvariants. The major associated conditions were all cardiovascular. This sort of study can highlight potential other indications for a drug targeting this pathway and suggest potential adverse events that might be experienced from targeting this pathway. Clearly, more and larger studies will be needed to truly understand the potential risks and benefits of a future drug targeting this pathway.  Continue reading

Patients With Highest LDL Levels Benefit Most From Lipid-Lowering Drugs

MedicalResearch.com Interview with:

Dr. Jennifer Robinson, MD MPH professor of epidemiology, University of Iowa College of Public Health. CREDIT Tom Langdon

Dr. Robinson

Dr. Jennifer Robinson, MD MPH
Professor, Departments of Epidemiology & Medicine
Director, Prevention Intervention Center
Department of Epidemiology
University of Iowa

MedicalResearch.com: What is the background for this study?

Response: Compared to previous placebo-controlled statin trials, the FOURIER trial where all patients were on high or moderate intensity statin, had no reduction in cardiovascular or total mortality and the reduction in cardiovascular events was less than expected.  However, other PCSK9 inhibitor trials performed in populations with higher baseline low density lipoprotein cholesterol (LDL-C) had cardiovascular risk reductions similar to that in the statin trails.

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Very High ‘Good Cholesterol’ HDL Linked To Increased Risk of Infections

MedicalResearch.com Interview with:

Børge G. Nordestgaard, MD, DMSc Professor, University of Copenhagen Chief Physician, Dept. Clinical Biochemistry Herlev and Gentofte Hospital Copenhagen University Hospital, Denmark

Prof. Nordestgaard

Børge G. Nordestgaard, MD, DMSc
Professor, University of Copenhagen
Chief Physician, Dept. Clinical Biochemistry
Herlev and Gentofte Hospital
Copenhagen University Hospital, Denmark 

MedicalResearch.com: What is the background for this study?

Response: For decades research into the role and function of high-density lipoprotein (HDL) has revolved around the believe that HDL protects against atherosclerotic cardiovascular disease. However, results from large genetic studies and from large randomized clinical trials with HDL cholesterol elevating drugs have all indicated that there is no causal association between HDL cholesterol and risk of atherosclerotic cardiovascular disease.

Given the hitherto strong focus on cardiovascular disease, little is known about the possible role of HDL in other aspects of human health and disease. Preclinical evidence has indicated that HDL might be of importance for normal function of the immune system and susceptibility to infectious disease, but it had never previously been investigated if levels of HDL cholesterol is associated with the risk of infectious disease in individuals from the general population. In the present study we tested this hypothesis in more than 100.000 Danes from the population at large.

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Statins: Large Disparity Between US/Canadian/UK and European Guidelines

MedicalResearch.com Interview with:

Borge G. Nordestgaard,

Borge G. Nordestgaard

Børge G. Nordestgaard, MD, DMSc
Department of Clinical Biochemistry
Herlev and Gentofte Hospital, Copenhagen University Hospital
Herlev, Denmark

MedicalResearch.com: What is the background for this study?

Response: Five major organizations recently published guidelines for using statins to prevent atherosclerotic cardiovascular disease  — the American College of Cardiology/American Heart Association (ACC/AHA) in 2013, the United Kingdom’s National Institute for Health and Care Excellence (NICE) in 2014, and in 2016 the Canadian Cardiovascular Society (CCS), the US Preventive Services Task Force (USPSTF), and the European Society of Cardiology/European Atherosclerosis Society (ESC/EAS). We applied these five guidelines to a contemporary study cohort of 45,750 40-75 year olds from the Copenhagen General Population Study.

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Praluent May Reduce Need For Apheresis In Some Patients With Familial Hypercholesterolemia

MedicalResearch.com Interview with:

Dr. Jay Edelberg VP Head of CV Development and Head Global CV Medical Affairs

Dr. Edelberg

Dr. Jay Edelberg MD, PhD
VP Head of CV Development and
Head Global CV Medical Affairs
Sanofi 

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Patients with heterozygous familial hypercholesterolemia (HeFH) are often not able to achieve their target low-density lipoprotein cholesterol (LDL-C) levels, and some may require lipoprotein apheresis (LA) to lower their “bad cholesterol.” Apheresis is a procedure similar to kidney dialysis, where bad cholesterol is mechanically removed from the blood. It is an invasive, expensive, and time-consuming treatment for patients, as well as physicians.

The Phase III ESCAPE clinical study looked at the potential effect of LA on total Praluent, free and total PCSK9 concentrations, as well as the combined pharmacodynamics effect of total Praluent on LDL-C-lowering.

Praluent levels remained unaffected by apheresis, and Praluent consistently suppressed free PCSK9 levels in patients with HeFH, regardless of LA treatment. This analysis further confirms clinical ESCAPE data that Praluent can be used in conjunction with LA and may reduce or potentially eliminate the need for LA in some patients.

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Cellular Protein Nrf1 Protects Against Fatty Liver

MedicalResearch.com Interview with:

Gokhan S. Hotamisligil MD PhD

Dr. Hotamisligil

Gokhan S. Hotamisligil MD PhD
J.S. Simmons Professor of Genetics and Metabolism
Chair, Department of Genetics and Complex Diseases
Department of Genetics and Complex Diseases
Department of Nutrition
Harvard Stem Cell Institute

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Cholesterol is often considered a ‘bad’ nutrient, as it has been strongly linked to a cluster of metabolic diseases. In reality however, cholesterol is absolutely vital for the health of all animal cells, serves as an essential building block for all membranes and precursor for essential molecules.  It usually only becomes toxic when cells are exposed to high levels or free forms of cholesterol or when it is stored in excess.

The reasons why cholesterol over-accumulates or causes excessive damage in cells of some people is not entirely clear, as cells are normally should be able to remove such excesses, and there remains key mechanistic gaps in our understanding of how cells control the molecular process of sensing excess cholesterol, engage ways of removal and launch countermeasures to defend their integrity. Filling this gap may reveal a new path toward alleviating the burden of cholesterol-related diseases.

To this end, we identified a new signal pathway mediated by a protein called Nrf1, which enables cells to know when to remove cholesterol, thereby preventing excess cholesterol storage. We show that Nrf1 directly senses cholesterol in a strategic subcellular compartment called the endoplasmic reticulum and coordinates an adaptive and defensive responses that protects the cells and promotes the removal of cellular cholesterol. Continue reading

Praluent Plus Statins Reduce LDL In High Risk Cardiovascular Patients

MedicalResearch.com Interview with:

VP Head of Cardiovascular Development and Head Global Cardiovascular Medical Affairs Sanofi

Dr. Edelberg

Dr. Jay Edelberg MD, PhD
VP Head of Cardiovascular Development and
Head Global Cardiovascular Medical Affairs
Sanofi 

MedicalResearch.com: What should readers take away from the data that Sanofi and Regeneron is presenting at ESC Congress 2017?   

Response: This year at European Society of Cardiology (ESC,) we are pleased to present analyses that further demonstrate additional efficacy and tolerability of Praluent (alirocumab).

While statins remain the first-line treatment, Praluent has shown a consistent benefit as an additional therapy to high-intensity statins in patients with clinical atherosclerotic cardiovascular disease (ASCVD) and/or heterozygous familial hypercholesterolemia (HeFH), allowing many patients to achieve low-density lipoprotein (LDL) cholesterol levels previously considered unattainable in this patient population.

Our data further emphasize the need for additional cholesterol-lowering options in these high cardiovascular (CV) risk patient populations, including individuals living with diabetes 

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Positive Emotions Predict Health Lipid Profiles In Western, But Not Eastern Cultures

MedicalResearch.com Interview with:

Jiah Yoo Ph.D. Student in Social Psychology University of Wisconsin-Madison Madison, WI 53706 

Jiah Yoo

Jiah Yoo
Ph.D. Student in Social Psychology
University of Wisconsin-Madison
Madison, WI 53706 

MedicalResearch.com: What is the background for this study?

Response: A growing number of studies have shown that positive emotions predict better physical health. However, a caveat of these findings is that most studies have been conducted with Western samples. As cultural psychologists, we have learned that European American cultural contexts are particular in that positive emotions are highly valued and emphasized. For example, in East Asian cultures, it is a commonly shared view that positive emotions have some dark sides such as that they are fleeting, may attract unnecessary attention from others, and can be a distraction from focusing on important tasks. Given the cultural differences in emotions, we thought it would be important to test whether the established link between positive emotion and enhanced physical health are relevant to other cultural contexts, such as those in East Asia.

We focused on blood lipids profiles, one of the major risk factors for heart diseases, as objective measures of health. Because of the global prevalence of coronary artery diseases, blood lipids are considered important indices of biological health in many Western and East Asian countries. In addition, blood lipids are largely influenced by lifestyles and behavioral factors so we further tested the role of various health behaviors (i.e., dietary habits, body mass index, smoking, alcohol consumption) in the lipids-emotion link in different cultures.

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Hyperlipidemia Linked To Lower Breast Cancer Mortality, Perhaps Due To Statin Therapy

MedicalResearch.com Interview with:

Dr Rahul Potluri Senior author and founder of the ACALM Study Unit Aston Medical School Aston University Birmingham, UK

Dr. Potluri

Dr Rahul Potluri
Senior author and founder of the ACALM Study Unit
Aston Medical School
Aston University
Birmingham, UK

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: The links between hyperlipidaemia and cancer has been exciting scientists in recent years.  We have previously shown an association with breast cancer and hyperlipidaemia using a cross-sectional dataset in 2014.

In 2016 we showed that in patients with the four main cancers in the UK (namely Breast, Lung, Colon and Prostate) that the presence of hyperlipidaemia improved the long term mortality and prognosis of these patients.  In this study utilising a big data, longitudinal study methodology, we looked at 16043 healthy women above the age of 40 with hyperlipidaemia and compared these to an age and gender matched control sample of 16043 healthy women without high cholesterol. We then followed up these patients and found that subsequent breast cancer rates in the women with hyperlipidaemia were 45% lower. Subsequent mortality in those patients who developed breast cancer was also 40% lower in the hyperlipidaemia group compared to the non-hyperlipidaemia controlled sample.

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Even After Rebates, Use of PCSK9 Inhibitor Would Still Cost Over $5 Million To Prevent One Stroke

MedicalResearch.com Interview with:

Inmaculada Hernandez, PharmD, PhD Assistant Professor of Pharmacy and Therapeutics University of Pittsburgh School of Pharmacy Pittsburgh, PA 1526

Dr. Hernandez

Inmaculada Hernandez, PharmD, PhD
Assistant Professor of Pharmacy and Therapeutics
University of Pittsburgh School of Pharmacy
Pittsburgh, PA 1526

MedicalResearch.com: What is the background for this study?

Response: A few months ago, the results of the FOURIER trial were published. This trial was the first one to evaluate the efficacy of PCSK9 inhibitors in the prevention of cardiovascular events, since the approval of these agents was based on trials that evaluated their efficacy in reducing levels of LDL-C. The results of the FOURIER trial did not meet the expectations generated by prior studies that had simulated how much the risk of cardiovascular events should decrease based on the observed reduction in LDL-C levels. A few hours after the publication of the results of the FOURIER trial, Amgen (evolocumab´s manufacturer) announced that it would be willing to engage in contracts where the cost of evolocumab would be refunded for those patients who suffer a heart attack or a stroke while using the drug.

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PCSK9 Inhibitor Praluent Added to Statins Improved Lipid Profile in Diabetes

MedicalResearch.com Interview with:

Dr-Robert-R-Henry.jpg

Dr. Henry

Robert R. Henry, M.D.
Professor of Medicine
Member of the ODYSSEY DM Steering Committee and
Director of the Center for Metabolic Research
VA San Diego Healthcare System

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: The ODYSSEY DM-DYSLIPIDEMIA trial was a randomized, open-label, parallel-group study designed to evaluate the superiority of Praluent versus usual care in 413 patients with type 2 diabetes with mixed dyslipidemia at high cardiovascular (CV) risk, not adequately controlled with maximally tolerated dose (MTD) statins. The primary endpoint was percent change in non-high-density lipoprotein cholesterol (non-HDL-C) from baseline to week 24.

In ODYSSEY DM-DYSLIPIDEMIA, Praluent 75 mg was added to MTD statins, with dose adjusted at week 12 to 150 mg every two weeks if their non-HDL-C was greater than or equal to 100 mg/dL at week 8. Approximately 64 percent of patients reached their lipid goals with the Praluent 75 mg dose.

Results from the ODYSSEY DM-DYSLIPIDEMIA study found that Praluent added to MTD statins showed significant reduction in non-HDL-C and other lipid parameters compared to those on usual care.

Praluent was superior to usual care in lowering non-HDL-C (37.3 percent and 4.7 percent, for the usual care arm). The mean difference between the two treatment arms was -32.5 percent (p<0.0001).

Praluent in combination with MTD statins reduced LDL-C by 43 percent from baseline compared to a 0.3 percent increase for usual care (p<0.0001). Treatment with Praluent also improved the overall lipid profile.

There is a large unmet need for improving cholesterol lowering in patients with diabetes. Despite current standard of care, nearly 70 percent of people age 65 or older with diabetes die from some form of heart disease; and 16 percent die of stroke. Furthermore, in spite of current standard of care, many people with diabetes continue to have persistent lipid abnormalities resulting in high residual CV risk.

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Adding Praluent (Alirocumab) To Statins Reduces LDL in High Cardiovascular Risk Diabetics

MedicalResearch.com Interview with:

Lawrence Leiter, M.D. MDCM, FRCPC, FACP, FACE, FAHA Chair of the ODYSSEY DM Steering Committee and Director of the Lipid Clinic at the Li Ka Shing Knowledge Institute St. Michael’s Hospital University of Toronto, Canada

Dr. Lawrence Leiter

Lawrence Leiter, M.D. MDCM, FRCPC, FACP FACE, FAHA
Chair of the ODYSSEY DM Steering Committee and
Director of the Lipid Clinic at the Li Ka Shing Knowledge Institute
St. Michael’s Hospital
University of Toronto, Canada

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: The ODYSSEY DM-INSULIN trial was a randomized, double-blind, placebo-controlled, multicenter study that evaluated alirocumab (Praluent) in 517 patients with insulin treated type 1 and type 2 diabetes with high cardiovascular (CV) risk and hypercholesterolemia despite maximally tolerated dose (MTD) statins. The primary endpoint was percent change in calculated LDL-C from baseline to week 24.

Alirocumab 75 mg every two weeks was added to MTD statins, with the dose increased at week 12 to 150 mg every two weeks if the LDL-C at week 8 was greater than or equal to 70 mg/dL. In fact, only about 20% of the alirocumab treated participants required the higher dose.

Results of the type 2 diabetes study population (n=441) showed that the addition of alirocumab to MTD statin therapy, reduced LDL-C by 48.2 percent from baseline compared to a 0.8 percent increase for placebo. The mean difference between the two treatment arms was -49 percent (p<0.0001). Treatment with alirocumab also improved the overall lipid profile. Furthermore, no new safety issues were identified.

There is a large unmet need for improving cholesterol lowering in patients with diabetes. Despite current standard of care, nearly 70 percent of people age 65 or older with diabetes die from some form of heart disease; and 16 percent die of stroke. Additionally, in spite of current standard of care, many people with diabetes continue to have persistent lipid abnormalities resulting in high residual CV risk.

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Cholesterol Uptake Capacity, a New Indicator of HDL Functionality, for Cardiovascular Risk Stratification in the Real World.

MedicalResearch.com Interview with:
Amane Harada, PhD
Senior Researcher
Central Research Laboratories, Sysmex Corporation
Kobe, Japan

Ryuji Toh, MD, PhD Associate Professor Division of Evidence-based Laboratory Medicine Kobe University Graduate School of MedicineRyuji Toh, MD, PhD
Associate Professor
Division of Evidence-based Laboratory Medicine
Kobe University Graduate School of Medicine
Kobe, Japan 


MedicalResearch.com: What is the background for this study?

Response: High-density lipoprotein (HDL) exhibits a variety of anti-atherogenic functions including anti-inflammatory and anti-oxidative functions as well as promoting reverse cholesterol transport. However, it has been reported that HDL may lose its anti-atherogenic properties and become “dysfunctional” HDL under pathological conditions.

Recent studies have demonstrated that cholesterol efflux capacity of HDL is a better predictor of CVD than HDL-C, suggesting that not only the quantity, but also the quality of HDL may significantly modulate and predict the progression of cardiovascular disease.

However, the conventional procedure for efflux capacity assay requires radiolabeling and cells, and the procedures are time consuming. Therefore, its clinical application is impractical.

To solve those problems, we have recently developed a new assay system to evaluate the capacity of HDL to accept cholesterol, named “uptake capacity”.

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Improving Statin Adherence Would Reduce Need For Expensive PCSK9 Inhibitors

MedicalResearch.com Interview with:
Julia M. Akeroyd, MPH

Center for Innovations in Quality, Effectiveness, and Safety (IQuESt)
Michael E. DeBakey Veteran Affairs Medical Center
Salim S Virani, MBBS, Ph.D.
Baylor College of Medicine

MedicalResearch.com: What is the background for this study?

Response: In the recently published Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) trial, treatment with evolocumab resulted in a 15% relative (1.5% absolute) risk reduction of major cardiovascular events in patients with atherosclerotic cardiovascular disease (ASCVD) at a median follow-up of 2.2 years. Given the high cost of evolocumab, there is a need to identify what proportion of ASCVD patients would qualify for evolocumab based on FOURIER entry criteria and how eligibility would change if maximal doses of evidence-based lipid lowering therapies were required.

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Many Eligible Groups Not Receiving Recommended Statin Therapy

MedicalResearch.com Interview with:
Dr. Yashashwi Pokharel MD, MSCR
Department of Cardiovascular Research
Saint Luke’s Mid-America Heart Institute
Kansas City, Missouri and
Salim S. Virani, MD PhD, FACC, FAHA
Associate Professor, Section of Cardiovascular Research
Associate Director for Research, Cardiology Fellowship Training Program
Baylor College of Medicine
Investigator, Health Policy, Quality and Informatics Program
Michael E. DeBakey Veterans Affairs Medical Center HSR&D Center of Innovation
Staff Cardiologist, Michael E. DeBakey Veterans Affairs Medical Center
Houston, TX

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Unlike the previous cholesterol management guideline that recommended use of either statin and non-statin therapy to achieve low density lipoprotein cholesterol (LDL-C) target, the 2013 American College of Cardiology/American Heart Association cholesterol management guideline made a major paradigm shift by recommending statin focused treatment in 4 specific patient groups and replaced LDL-C target with fixed statin intensity treatment (moderate to high intensity statin therapy).

With this change, it was speculated that a large number of patients would be eligible for statin treatment (in one study, up to 11.1% additional patients were expected to be eligible for statin therapy). Our study provided the real world trends in the use of statin and non-statin lipid lowering therapy (LLT) from a national sample of cardiology practices in 1.1 million patients 14 months before and 14 months after the release of the 2013 guideline.

We found a modest, but significant increasing trend in the use of statin therapy in only 1 of the 4 patient groups eligible for statin therapy (i.e., 4.3% increase in the use of moderate to high intensity statin therapy in patients with established atherosclerotic cardiovascular disease). We did not find any significant change in non-statin LLT use. Importantly, about a third to half of patients in statin eligible groups were not receiving moderate to high intensity statin therapy even after the publication of the 2013 guideline.

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PCSK9 Inhibition with Alirocumab Increases Removal of LDL Cholesterol

MedicalResearch.com Interview with:
Henry N. Ginsberg, MD

Irving Institute for Clinical and Translational Research
Columbia University
Columbia College of Physicians and Surgeons
New York, NY

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Previous studies in mice and cells have identified increased hepatic low density lipoprotein (LDL) receptors as the basis for LDL lowering by PCSK9 inhibitors, but there have been no human studies characterizing the effects of PCSK9 inhibitors on lipoprotein metabolism, particularly effects on very low density lipoproteins (VLDL), intermediate density lipoproteins (IDL) or LDL metabolism.

This study in 18 healthy subjects, found that alirocumab decreased the number of IDL and LDL particles in the circulation, and their associated cholesterol and apoB levels by increasing efficiency of the clearance of IDL and LDL. There were not effects on VLDL metabolism. The increased clearance of IDL meant that less LDL was produced from IDL, which is the precursor of LDL. Thus, the dramatic reductions in LDL cholesterol resulted from both less LDL being produced and more efficient clearance of LDL. These results are consistent with increases in LDL receptors available to clear IDL and LDL from blood during PCSK9 inhibition.

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Meta-analysis of Long-Chain Omega-3 Fatty Acids and Coronary Heart Disease Risk

MedicalResearch.com Interview with:
Dominik D Alexander, PhD, MSPH

Principal Epidemiologist
EpidStat Institute
Ann Arbor, MI Seattle, WA

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: In recent years, the body of scientific literature on n-3 LCPUFA (EPA/DHA) intake and coronary heart disease (CHD) risk has exploded with mixed results. It was only logical to conduct a comprehensive meta-analysis of randomized controlled trials (RCTs) to estimate the effect of EPA+DHA on CHD, and to conduct a comprehensive meta-analysis of prospective cohort studies to estimate the association between EPA+DHA intake and CHD risk.

Among RCTs, there was a nonstatistically significant reduction in CHD risk with EPA+DHA
provision (SRRE=0.94; 95% CI, 0.85-1.05). Subgroup analyses of data from RCTs indicated a statistically significant CHD risk reduction with EPA+DHA provision among higher-risk populations, including participants with elevated triglyceride levels (SRRE=0.84; 95% CI, 0.72-0.98) and elevated low-density lipoprotein cholesterol (SRRE=0.86; 95% CI, 0.76-0.98). Meta-analysis of data from prospective cohort studies resulted in a statistically significant SRRE of 0.82 (95% CI, 0.74-0.92) for higher intakes of EPA+DHA and risk of any CHD event.

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Some Type 2 Diabetics May Benefit From Adding Fenofibrate To Statins

MedicalResearch.com Interview with:

Marshall B. Elam PhD MD Professor Pharmacology and Medicine (Cardiovascular Diseases) University of Tennessee Health Sciences Center Memphis

Dr. Marshall B. Elam

Marshall B. Elam PhD MD
Professor Pharmacology and Medicine
(Cardiovascular Diseases)
University of Tennessee Health Sciences Center
Memphis

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: This manuscript presents the findings of extended follow up of patients with Type 2 Diabetes who were treated with fenofibrate, a member of a group of triglyceride lowering medications known as fibrates or PPAR alpha agonists, as part of the Action to Control Cardiovascular Risk in T2DM (ACCORD) study.

ACCORD was designed to test the effect of intensive treatment of cardiovascular risk factors including blood glucose, blood pressure and lipids on risk of heart attack, stroke and cardiac death in patients with Type 2 Diabetes.

The lipid arm of ACCORD tested the hypothesis that adding fenofibrate to statin therapy would further reduce risk of these cardiovascular events.

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Familial Hypercholesterolemia Diagnosed Through EHR and Genetics Data

MedicalResearch.com Interview with:

Michael F. Murray MD Geisinger Health System Danville, PA 17822

Dr. Michael Murray

Michael F. Murray MD
Geisinger Health System
Danville, PA 17822

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: The DiscovEHR cohort was formed as a result of a research collaboration between Geisinger Health System and Regeneron Pharmaceuticals. There are over 50,000 patient participants in the cohort who have volunteered to have their de-identified genomic sequence data linked to their de-identified EHR data for research purposes. We report in this paper findings around the identification of 229 individuals (1:256) with pathogenic or likely pathogenic variants in one of the three genes (LDLR, APOB, PCSK9) associated with Familial Hypercholesterolemia (FH). The study found that these individuals are unlikely to carry a diagnosis of FH and are at risk for early coronary artery disease.

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PCSK9 Inhibitor Praluent Substantially Reduced LDL-C Cholesterol

MedicalResearch.com Interview with:

Dr. Eli M. Roth MD, FACC President, Medical Director Sterling Research Group Cincinnati, OH

Dr. Eli Roth

Dr. Eli M. Roth MD, FACC
President, Medical Director
Sterling Research Group
Cincinnati, OH

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: At this year’s AHA 2016, we presented a pharmacodynamics analysis of ODYSSEY CHOICE I, which evaluated the effects of Praluent 300 mg administered every four weeks (Q4W) for 24 weeks in hypercholesterolemia patients at moderate to very high cardiovascular risk who were on maximally tolerated statin or no statin and/or other lipid-lowering therapies.

The pharmacodynamic analysis of CHOICE I in patients on statins supports the use of Praluent 300 mg Q4W as an alternative starting dose for patients who prefer a Q4W dosing regimen and demonstrates the value of LDL-C based dosing interval adjustment. The findings from this analysis were consistent with prior ODYSSEY Phase 3 studies, showing that Praluent substantially reduced circulating free PCSK9 concentration, resulting in significant LDL-C reductions. Additionally, Praluent was generally well tolerated.

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Byproduct of Sweet Potato Waste Offers Clue To Lipid Metabolism

MedicalResearch.com Interview with:
Dr. Koji Ishiguro

National Agriculture and Food Research Organization
Japan

MedicalResearch.com: What is the background for this study?

Response: -Sweet potato (Ipomoea batatas L.) roots are not only used for human consumption, they are used to make starch materials, processed foods, and distilled spirits in Japan. Starch use accounts for about 15% (131,500 tons) of total sweet potato production. Starch residues are discharged during starch production and are mainly used in animal feed and compost. Large amounts of the wastewater, which can cause serious environmental problems, are discarded after clarification. Investigation into the uses of the by-products of the sweet potato starch industry would benefit both the environment and industry.

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